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The agouti (a) locus in mouse chromosome 2 normally regulates coat color pigmentation. The mouse agouti gene was recently cloned and shown to encode a distinctive 131-amino acid protein with a consensus signal peptide. Here we describe the cloning of the human homolog of the mouse agouti gene using an interspecies DNA-hybridization approach. Sequence analysis revealed that the coding region of the human agouti gene is 85% identical to the mouse gene and has the potential to encode a protein of 132 amino acids with a consensus signal peptide. Chromosomal assignment using somatic-cell-hybrid mapping panels and fluorescence in situ hybridization demonstrated that the human agouti gene maps to chromosome band 20q11.2. This result revealed that the human agouti gene is closely linked to several traits, including a locus called MODY (for maturity onset diabetes of the young) and another region that is associated with the development of myeloid leukemia. Initial expression studies with RNA from several adult human tissues showed that the human agouti gene is expressed in adipose tissue and testis.
mStaf is a zinc-finger protein that activates the transcription of the mouse selenocysteine tRNA gene. The mStaf gene is approx. 35 kb long and split into 16 exons. All exon-intron junction sequences conform to the GT/AG rule. The transcription start site is located 83 bp upstream of the initiation codon. Chromosomal mapping localized the gene to mouse chromosome 7, region E3-F1. Sequence analysis of the proximal promoter region revealed several potential regulatory elements; these include the recognition elements of Sp1, Nkx, CP2, E2A, SIF (SIS-inducible factor), TFII-I and cAMP-responsive element (CRE), but no TATA sequences. Transfection experiments demonstrated that the 5'-flanking region (-1894 to +37) of the mStaf gene drives transcription in mouse NMuMG cells and that a construct containing a fragment from -387 to +37 showed the highest transcriptional activity. Deletion and mutation experiments suggested that four Sp1 sites played an important role for the basal promoter activity. Furthermore, electrophoretic mobility-shift assays demonstrated that Sp3 but not other Sp (specificity protein) family members binds to three of the Sp1 sites. Our present study suggests that Sp3 is involved in the basal transcriptional activation of the mStaf gene.
A novel cDNA encoding a putative Ser/Thr protein kinase was isolated from a human skeletal muscle cDNA library. It contains an open reading frame that extends from nt 104 to 1510 and codes for a protein of 469 amino acids. A catalytic domain containing the conserved residues of the Ser/Thr protein kinase, especially human ribosome protein S6 kinase (RSK), was found to be located in the C-terminal end of the deduced protein. The gene was mapped to human chromosome 12q12-q13.1 by fluorescence in situ hybridization, and this result was confirmed with the Radiation Hybrid GB4 panel. Northern hybridization showed that the novel gene is expressed in all 16 human tissues tested with especially strong expression in testis, skeletal muscle, and brain, whereas weak expression was detected in kidney, thymus, small intestine, liver, lung, heart, and colon.
We have determined the chromosomal location of the genes for the human keratin intermediate filament proteins K1 (type II; 67 kDa) and K10 (type I; 57 kDa) by the use of specific cDNA clones in conjunction with somatic cell hybrid analysis and in situ hybridization. The K1 keratin gene maps to chromosome region 12q11----q13; the K10 keratin gene maps to chromosome region 17q12----q21. Each gene has been mapped relative to other genes known to be localized on chromosomes 12 and 17, respectively. In somatic cell hybrid analysis, the K1 gene segregates concordantly with the Hox-3 homeo box gene cluster at chromosome region 12p12----q13. The K10 gene localizes to a region proximal to a breakpoint at 17q21 which is involved in a t(17;21)(q21;q22) translocation associated with an acute leukemia. K10 appears to be distal (telomeric) to the gene loci for G-CSF, erb-A, and Her-2, which map to chromosome region 17q12----q21. The NGFR gene and Hox-2 homeo box locus are localized distal to the 17q21 break point and thus distal to the K10 gene. These data demonstrate that keratin genes K1 and K10, which are coexpressed in terminally differentiated epidermis, are not linked in the human genome, implying the existence of trans-acting factors involved in the regulation of expression of these genes.
The estrogen-related receptors ERRalpha and ERRbeta (formerly ERR1 and ERR2) form a subgroup of the steroid/thyroid/retinoid receptor family. ERRalpha and ERRbeta are homologous to the estrogen receptor and bind similar DNA targets; however, they are unable to activate gene transcription in response to estrogens. We have used interspecific backcross analysis to map the murine Estrra locus to chromosome 19 and Estrrb to mouse chromosome 12. Using fluorescence in situ hybridization, we have mapped the human ESRRA gene to chromosome 11q12-q13 and the human ESRRB gene to chromosome 14q24.3. In addition, we report the isolation of a processed human ERRalpha pseudogene mapping to chromosome 13q12.1. To our knowledge, this represents the first report of a pseudogene associated with a member of the nuclear receptor superfamily.
The murine retinoid X receptor beta (mRXR beta) is a nuclear hormone receptor that activates transcription of murine major histocompatibility complex (MHC) class I genes in response to retinoic acid. In this study, the human RXR beta gene was mapped onto the short arm or centromeric region of chromosome 6 (6pter-q13), which also harbors the MHC. Chromosomal localization was performed by Southern hybridization of genomic DNA from human rodent cell hybrids with the mRXR beta gene as a probe. In addition, a full-length cDNA clone encoding a human RXR beta was isolated by nucleic acid screening of a human cDNA library with a fragment of the mRXR beta gene as a probe. Comparison of the nucleotide-coding sequences of the human and the murine RXR beta revealed a predominance of third base substitutions, resulting in selective conservation of the predicted amino acid sequence of the proteins. The overall sequence homology was 97.6% on the amino acid level as opposed to 91.6% on the nucleotide level. In Northern hybridization experiments with the human cDNA as a probe, RXR beta gene transcripts were detected in a variety of human tumor cell lines, regardless of whether these cell lines expressed MHC class I genes.
The chromosomal localization of the human Mu class glutathione S-transferase (GST) genes has been complicated by two factors; the total number of genes is unknown and there is a polymorphism that results from the presence or absence of the GSTM1 gene. Three human Mu class glutathione S-transferase isoenzymes, GSTM1, GSTM2, and GSTM3, have been characterized previously, and we have recently cloned and characterized GSTM4, another member of this class. Here we report that a probe derived from GSTM4 cross-hybridizes with the other three known human Mu class GST genes. In situ hybridization with the GSTM4 probe localized a major region of hybridization on chromosome band 1p13. Although there is a region of very weak hybridization on chromosome 6, these data indicate that the human Mu class gene family is largely clustered and not dispersed on different chromosomes. The identical hybridization patterns in individuals with or without the GSTM1 gene suggest that this locus is a component of the Mu class GST gene cluster.
Developmental cytogenetic analyses of Xenopus tropicalis larvae from two origins were performed on stage 27-34 heads treated with colchicine. Standard G-band karyotyping using trypsin and chromosome mapping of 184 bands were examined. Although the main karyotype was 2n = 20, polyploidy (3n = 30 or 4n = 40) and aneuploidy were detected in each individual treated with colchicine, even those treated for only 1 h. The percentage of polyploid karyotypes was 10-20% across the total of measured metaphases. The mean mitotic index was 0.10. Chromosomal breaks and exchanges were detected at the secondary constriction of chromosomes 5 or 6. Ag-band detection showed clearly positive staining at the secondary constriction of chromosome 5, which corresponds to the nucleolar organizer region. Tandem duplication of negative G-bands at the secondary constriction of chromosome 6 and the short arm of chromosome 10 was suggested by this study. X. tropicalis thus provides a good model to study the mechanism and effects of chromosomal abnormalities, gene mapping and tissue specific gene expression in the developmental process.
The histamine H3 receptor (H3R) was recently cloned, and two isoforms, termed H3L and H3S, differing in the third intracytosolic loop, were isolated but the chromosomal mapping and organization of its gene remained unknown. PCR analysis of a human x rodent cell hybrid panel indicated that the H3R gene is located in the telomeric region of chromosome 20q. Alignment of human H3R cDNA sequences with DNA sequences of this chromosome revealed that its coding region comprises three exons interrupted by two introns located in the second transmembrane domain (TM2) and second intracytosolic loop, respectively. Thus the organization of the H3R gene indicates that the H3L and H3S isoforms, that we characterized not only in rodents but also in humans, are generated by retention and deletion, respectively, of a pseudo-intron located in the third intracytosolic loop.
Standard photographic maps of the polytene chromosomes are presented for the melon fly Bactrocera cucurbitae, a serious pest of fleshy fruits and vegetables. Five larval salivary gland polytene chromosomes (10 polytene arms) were isolated, and their characteristic features and landmarks have been recognized. Banding patterns of each of the polytene arms are presented, where variation in band intensity and puffs appear to reflect fundamental differences in chromosomes. The whole polytene genome has been typically mapped by dividing it into 100 sections and the subsections were lettered. The mitotic chromosomes of larval brain ganglia are also examined, five pairs of autosomes and an XX/XY sex chromosome pair. In addition, a heterochromatic mass corresponding to the sex chromosomes are observed in the polytene nuclei of salivary gland tissue. This investigation showed that B. cucurbitae has excellent cytological material for polytene chromosome analysis and proved to be very useful for obtaining more detailed genetic information on the pest's natural populations.
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The disease outcome in malaria caused by the protozoan parasite Plasmodium is influenced by host genetic factors. To identify host genes conferring resistance to infection with the malaria parasite, we undertook chromosomal mapping using a whole-genome scanning approach in cross-bred mice. NC/Jic mice all died with high parasitemia within 8 days of infection with 1 x 10(5) parasitized erythrocytes. In contrast, 129/SvJ mice all completely excluded malaria parasites from the circulation and remained alive 21 days after infection. We performed linkage analysis in backcross [(NC/Jic x 129/SvJ)xNC/Jic] mice. The Pymr ( Plasmodium yoelii malaria resistance) locus was mapped to the telomeric portion of mouse Chromosome (Chr) 9. This locus controls host survival and parasitemia after infection. The Char1 locus ( P. chabaudi resistance locus 1), controlling host survival and peak parasitemia in P. chabaudi infection, was previously mapped to the same region. This host resistance locus mapping to Chr 9 may represent a ubiquitous locus controlling susceptibility to rodent malaria. Elucidation of the function of this gene will provide valuable insights into the mechanism of host defense against malaria parasite infection.
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We have recently described the isolation of a cDNA encoding an enzyme thought to be involved in the degradation of insulin by insulin-responsive tissues. This enzyme, referred to as insulin-degrading enzyme (IDE), is a cytosolic proteinase of 110,000 mol wt which shares structural and functional homology with bacterial protease III. The enzyme may function in the termination of the insulin response. We report here the mapping of the human and mouse IDE genes to human chromosome 10 and mouse chromosome 19, respectively, and evidence for the existence of a single complex IDE gene. We also describe the stable transfection of Chinese hamster ovary cells with a plasmid containing the IDE cDNA under the transcriptional control of the SR alpha promoter. The recombinant protein synthesized by these cells is indistinguishable from the isolated human enzyme in both its size and immunoreactivity and degrades insulin with a specific activity similar to that of the purified proteinase. Overexpression of IDE using this system should allow for a functional test of the role of IDE in insulin action. In addition, expression of various site-directed mutants of IDE will aid in identifying the residues of IDE and protease III that are essential to the activity of this unique family of proteinases.
The chromosome banding pattern has been analyzed in clones of mouse myeloid leukemic cells that differ in their ability to be induced to differentiate by the protein inducer MGI (macrophage and granulocyte inducer). None of the clones had a completely normal diploid banding pattern. The clones studied were either MGI+ (that can be induced to form Fc and C3 rosettes), a stage in the differentiation of myeloid cells, or MGI- (that cannot be induced to form these rosettes). All six cultured clones of MGI- cells from myeloid leukemias independently produced in six separate animals showed a loss of a piece of one chromosome 2 and this abnormal chromosome was maintained in leukemias derived from the cultured cells. This loss was not found in MGI+ clones or lymphoid leukemias. Five MGI+ mutants, derived from an MGI- clone with a loss of a piece of one chromosome 2, one normal chromosome 12, and two translocated chromosomes 12, maintained the abnormal chromosome 2 but lost either the one normal or one of these translocated chromosome 12. These results indicate that chromosomes 2 and 12 carry genes that control the differentiation of myeloid leukemic cells and that inducibility by MGI is controlled by the balance between these genes. We suggest that these chromosomes also carry genes that control the malignancy of these cells.